“Nal” opiates are a class of alkaloids containing tertiary amines which includes naltrexone, naloxone, nalbuphone, (+)-naltrexone, (+)-naloxone, (+)-nalbuphone, α- or β-naltrexol, α- or β-naloxol, and α- or β-nalbuphine. These opiates share a basic morphinan chemical structure and include a tertiary amine at position C-17. They are particularly useful as competitive antagonists of opioid compounds, and as such are widely used in treating substance abuse and addiction.
Tertiary amines can be synthesized via direct alkylation of secondary amines. For example, naltrexone can be synthesized via direct alkylation of noroxymorphone using cyclopropylmethylbromide as an alkylating agent. From a theoretical standpoint, the direct alkylation of secondary amines with alkyl halides is the most straight-forward method for the synthesis of tertiary amines. However, noroxymorphone is relatively costly and direct N-alkylation typically results in relatively poor yields of only about 60%-80%. Moreover, the direct route produces unacceptably high levels of undesired side products via the simultaneous but unwanted N-alkylation of tertiary amines, and also O-alkylation of the phenol group at position C-3. To reduce cost and improve yield, other synthetic routes have been sought and investigated. Indirect alkylation methods have been described, such as those involving metal-mediated N-alkylation or reductive amination of secondary amines. However, indirect methods are remain limited by relatively modest yields, and are further limited by the difficulty in completely removing the required toxic metal reagents, and by poor commercial availability of the required alkylation reagents (e.g., cyclopropylmethylaldhyde). Accordingly, a need exists for improved synthetic methods for producing morphinan compounds containing a tertiary amine.